Bone marrow transplantation in lethally irradiated mice was used to investigate immunogenetic factors affecting the severity of the graft-versus-host reaction. Immunologically competent cells derived from marrow grafts are able to distinguish qualitative and quantitative differences in expression of tissue antigens. An unresponsive state requires an equilbrium between the ability to respond and the antigenic expression of tissue antigens. Maternal influences produce phenotypic modifications in both the ability to respond and the expression of tissue antigenicity. This naturally occurring adaptive mechanism may be experimentally manipulated a) to improve survival by reducing the severity of the graft-versus-host reaction for purposes of a successful marrow graft or b) to specifically increase the immune response to produce a desired rejection as in the case of immunotherapy of tumors.